The Journal of Infectious Diseases EDITORIAL COMMENTARY
Humanized Mice—A Neoteric Animal Disease Model for Ebola Virus? Joseph Prescott and Heinz Feldmann Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana
(See the major article by Bird et al on pages 703–11.)
Keywords.
humanized mouse; animal model; Ebola virus.
Work on Ebola virus has gained momentum over the past year, largely due to the ongoing, unprecedented, and devastating outbreak in West Africa, with >28 500 clinical Ebola cases and 11 300 deaths [1]. Scientists, infectious diseases professionals, and the media have repeatedly warned that the West African virus strain, designated Ebola virus Makona, may be mutating more rapidly, with the potential for increased virulence or transmissibility [2]. Mutations could, indeed, affect important countermeasures, such as diagnostics, therapeutics, and vaccines, although there is currently little evidence for increased virulence or transmissibility [3]. Thus, it is of paramount importance to further investigate the West African Ebola virus strain, as well as other ebolaviruses, with the goal to better define the biological virus phenotypes and to develop advanced countermeasures. The best way to study the complex interactions between viruses and the host is by using animal models of disease. Several animal models exist for the study of Ebola virus pathogenesis [4, 5]; Table 1 summarizes the critical features of these models. Nonhuman primates (NHPs), especially cynomolgus and rhesus macaques, are considered the gold standard
Received and accepted 11 November 2015; published online 17 November 2015. Correspondence: H. Feldmann, Rocky Mountain Laboratories, 903 S 4th St, Hamilton, MT 59840 (feldmannh@niaid. nih.gov). The Journal of Infectious Diseases® 2016;213:691–3 Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jiv539
animal models for Ebola [6]. NHPs have the advantage of being more closely related than rodents to humans, and, thus, data gleaned from experiments are likely highly applicable to humans. Disease in NHPs best recapitulates the features seen in humans among all established animal models. Obvious drawbacks to the use of NHPs include ethical considerations, cost, and size. Before NHPs are used for experimentation, analysis of rodent models of Ebola, such as the mouse [7], the guinea pig [8], and the hamster [9], is generally promoted. Immunocompetent rodents, in particular the mouse, are inexpensive smallanimal models of Ebola; however, many aspects of these models make it difficult to draw conclusions about general pathogenesis and the efficacy of countermeasures in humans. The disease course is often different in rodents, with coagulopathies being a major hallmark in humans but almost nonexistent in mice or limited in guinea pigs. A few studies have used immunocompromised mouse models deficient in certain adaptive or innate immune responses (ie, interferon α/β receptor-knockout, STAT1-knockout, or severe combined immunodeficiency [SCID] mouse models) [10, 11]. These animals show lethal disease upon infection with adapted or wild-type Ebola virus, but disease progression is often slower with wild-type Ebola virus isolates. These models are not well established and are considered of limited use because of their immunocompromised status. However, until now, they represent the only rodent models that are susceptible to
wild-type isolates. The more recently developed hamster model seems to best recapitulate human disease among rodent models, but the use of hamsters, as well as guinea pigs, is hampered by the lack of species-specific immunological tools [12, 13]. A major drawback with all immunocompetent rodent models is that ebolaviruses, as well as the closely related marburgviruses, must be passaged or reverse engineered to generate an adapted isolate that causes disease. Genetic changes in the rodent-adapted viruses have been mapped to genes with interferon antagonistic functions, and adapted viruses are able to efficiently antagonize the rodent’s immune response [14, 15]. This brings into question whether the relationship between humans (and NHPs) and wild-type viruses is the same as between rodents and adapted viruses. The article by Bird et al in this issue of The Journal of Infectious Diseases describes the use of humanized mice as a model for Ebola virus infection and disease progression, using both a historic Central African isolate, as well as a contemporary Makona isolate. They show that mice devoid of their native immune response and reconstituted with a human innate and adaptive immune system are susceptible to infection and die of disease within approximately 2 weeks after inoculation with wild-type Ebola virus. They observed histological changes in the liver and upregulation of cytokines and chemokines, consistent with Ebola hemorrhagic fever. Unlike for native rodent models, wildtype Ebola virus was able to cause disease,
EDITORIAL COMMENTARY
•
JID 2016:213 (1 March)
•
691
Table 1.
Characteristics of Animal Models for Ebola Virus
Characteristic
Mouse
Immunocompromised Mouse
Guinea Pig
Hamster
Macaque
Humanized Mouse
Virus
Adapted
Wild type
Adapted
Adapted
Wild type
Virulence
High
High
High
High
High
High
Human disease characteristics
Some
Some
Some
More
Almost all
Not well studied
Disease course
Humanized Mice—A Neoteric Animal Disease Model for Ebola Virus? Joseph Prescott and Heinz Feldmann Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana
(See the major article by Bird et al on pages 703–11.)
Keywords.
humanized mouse; animal model; Ebola virus.
Work on Ebola virus has gained momentum over the past year, largely due to the ongoing, unprecedented, and devastating outbreak in West Africa, with >28 500 clinical Ebola cases and 11 300 deaths [1]. Scientists, infectious diseases professionals, and the media have repeatedly warned that the West African virus strain, designated Ebola virus Makona, may be mutating more rapidly, with the potential for increased virulence or transmissibility [2]. Mutations could, indeed, affect important countermeasures, such as diagnostics, therapeutics, and vaccines, although there is currently little evidence for increased virulence or transmissibility [3]. Thus, it is of paramount importance to further investigate the West African Ebola virus strain, as well as other ebolaviruses, with the goal to better define the biological virus phenotypes and to develop advanced countermeasures. The best way to study the complex interactions between viruses and the host is by using animal models of disease. Several animal models exist for the study of Ebola virus pathogenesis [4, 5]; Table 1 summarizes the critical features of these models. Nonhuman primates (NHPs), especially cynomolgus and rhesus macaques, are considered the gold standard
Received and accepted 11 November 2015; published online 17 November 2015. Correspondence: H. Feldmann, Rocky Mountain Laboratories, 903 S 4th St, Hamilton, MT 59840 (feldmannh@niaid. nih.gov). The Journal of Infectious Diseases® 2016;213:691–3 Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jiv539
animal models for Ebola [6]. NHPs have the advantage of being more closely related than rodents to humans, and, thus, data gleaned from experiments are likely highly applicable to humans. Disease in NHPs best recapitulates the features seen in humans among all established animal models. Obvious drawbacks to the use of NHPs include ethical considerations, cost, and size. Before NHPs are used for experimentation, analysis of rodent models of Ebola, such as the mouse [7], the guinea pig [8], and the hamster [9], is generally promoted. Immunocompetent rodents, in particular the mouse, are inexpensive smallanimal models of Ebola; however, many aspects of these models make it difficult to draw conclusions about general pathogenesis and the efficacy of countermeasures in humans. The disease course is often different in rodents, with coagulopathies being a major hallmark in humans but almost nonexistent in mice or limited in guinea pigs. A few studies have used immunocompromised mouse models deficient in certain adaptive or innate immune responses (ie, interferon α/β receptor-knockout, STAT1-knockout, or severe combined immunodeficiency [SCID] mouse models) [10, 11]. These animals show lethal disease upon infection with adapted or wild-type Ebola virus, but disease progression is often slower with wild-type Ebola virus isolates. These models are not well established and are considered of limited use because of their immunocompromised status. However, until now, they represent the only rodent models that are susceptible to
wild-type isolates. The more recently developed hamster model seems to best recapitulate human disease among rodent models, but the use of hamsters, as well as guinea pigs, is hampered by the lack of species-specific immunological tools [12, 13]. A major drawback with all immunocompetent rodent models is that ebolaviruses, as well as the closely related marburgviruses, must be passaged or reverse engineered to generate an adapted isolate that causes disease. Genetic changes in the rodent-adapted viruses have been mapped to genes with interferon antagonistic functions, and adapted viruses are able to efficiently antagonize the rodent’s immune response [14, 15]. This brings into question whether the relationship between humans (and NHPs) and wild-type viruses is the same as between rodents and adapted viruses. The article by Bird et al in this issue of The Journal of Infectious Diseases describes the use of humanized mice as a model for Ebola virus infection and disease progression, using both a historic Central African isolate, as well as a contemporary Makona isolate. They show that mice devoid of their native immune response and reconstituted with a human innate and adaptive immune system are susceptible to infection and die of disease within approximately 2 weeks after inoculation with wild-type Ebola virus. They observed histological changes in the liver and upregulation of cytokines and chemokines, consistent with Ebola hemorrhagic fever. Unlike for native rodent models, wildtype Ebola virus was able to cause disease,
EDITORIAL COMMENTARY
•
JID 2016:213 (1 March)
•
691
Table 1.
Characteristics of Animal Models for Ebola Virus
Characteristic
Mouse
Immunocompromised Mouse
Guinea Pig
Hamster
Macaque
Humanized Mouse
Virus
Adapted
Wild type
Adapted
Adapted
Wild type
Virulence
High
High
High
High
High
High
Human disease characteristics
Some
Some
Some
More
Almost all
Not well studied
Disease course
